Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis
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Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.38 × 10(-10)) and a rare synonymous variant in GFI1B (rs150813342, MAF = 0.009, discovery + replication p = 1.79 × 10(-27)). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that preferentially promotes megakaryocyte differentiation and platelet production. These results demonstrate how unbiased studies of natural variation in blood cell traits can provide insight into the regulation of human hematopoiesis.
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Interrogation of specific loci identified through studies of population-based variation has uncovered key regulatory mechanisms, such as the role of specific GFI1B isoforms in megakaryopoiesis or the identification of a distinct CEBPA enhancer involved in the production of basophils.
“In other cases, the interrogation of specific loci identified through studies of population-based variation has uncovered key regulatory mechanisms, such as the role of specific GFI1B isoforms in megakaryopoiesis or the identification of a distinct CEBPA enhancer involved in the production of basophils (Guo et al., 2017; Polfus et al., 2016).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Polfus et al., 2016
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Frydman, G. H., Pate, K. A. M., & Vitsky, A. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95488-4.00135-2
Thibord, F., Chen, M., & Johnson, A. D. (2025) · Springer eBooks · doi:10.1007/978-3-031-96340-7_26
Self-citationCPS1: a multipurpose mitochondrial enzyme, bile protein, acute liver injury biomarker, and cytokine
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Self-citationHereditary Thrombocytopenia: Pathophysiological Categories, Diagnosis and Treatment
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A polygenic etiology for inherited thrombocytopenias of unknown origin
Isidori, F., Melazzini, F., Santonastaso, F., Marconi, C., Bozzi, V., Barozzi, S., Mattiaccio, A., Giangregorio, T., Iovino, E., Palumbo, G., et al. (2026) · HemaSphere · doi:10.1002/hem3.70459
Self-citation
- Authors
- Polfus, L. M., Khajuria, R. K., Schick, U. M., Pankratz, N., Pazoki, R., Brody, J. A., Chen, M.-H., Auer, P. L., Floyd, J. S., Huang, J., Lange, L., van Rooij, F. J. A., Gibbs, R. A., Metcalf, G., Muzny, D., Veeraraghavan, N., Walter, K., Chen, L., Yanek, L., Becker, L. C., Peloso, G. M., Wakabayashi, A., Kals, M., Metspalu, A., Esko, T., Fox, K., Wallace, R., Franceschini, N., Matijevic, N., Rice, K. M., Bartz, T. M., Lyytikäinen, L.-P., Kähönen, M., Lehtimäki, T., Raitakari, O. T., Li-Gao, R., Mook-Kanamori, D. O., Lettre, G., van Duijn, C. M., Franco, O. H., Rich, S. S., Rivadeneira, F., Hofman, A., Uitterlinden, A. G., Wilson, J. G., Psaty, B. M., Soranzo, N., Dehghan, A., Boerwinkle, E., Zhang, X., Johnson, A. D., O’Donnell, C. J., Johnsen, J. M., Reiner, A. P., Ganesh, S. K., & Sankaran, V. G.
- Affiliations
- The University of Texas Health Science Center at Houston (US)
- Broad Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- University of Minnesota (US)
- Erasmus MC (NL)
- University of Washington (US)
- Boston University (US)
- University of Wisconsin–Milwaukee (US)
- Wellcome Sanger Institute (GB)
- University of North Carolina at Chapel Hill (US)
- Baylor College of Medicine (US)
- University of Cambridge (GB)
- Johns Hopkins University (US)
- Massachusetts General Hospital (US)
- University of Tartu (EE)
- University of Iowa (US)
- Tampere University (FI)
- Tampere University Hospital (FI)
- University of Turku (FI)
- Montreal Heart Institute (CA)
- University of Virginia (US)
- University of Mississippi Medical Center (US)
- Group Health Cooperative (US)
- National Heart, Lung, and Blood Institute (US)
- Bloodworks Northwest (US)
- University of Michigan (US)
- Corresponding author
- Sankaran, Vijay G.
- ORCID
- Polfus, Linda M.
- Khajuria, Rajiv K.
- Pankratz, Nathan
- Pazoki, Raha
- Brody, Jennifer A.
- Chen, Ming-Huei
- Auer, Paul L.
- Floyd, James S.
- Huang, Jie
- Gibbs, Richard A.
- Metcalf, Ginger
- Muzny, Donna
- Veeraraghavan, Narayanan
- Walter, Klaudia
- Chen, Lu
- Yanek, Lisa
- Becker, Lewis C.
- Peloso, Gina M.
- Kals, Mart
- Metspalu, Andres
- Esko, Tõnu
- Fox, Keolu
- Wallace, Robert
- Franceschini, Nora
- Rice, Kenneth M.
- Bartz, Traci M.
- Lyytikäinen, Leo-Pekka
- Kähönen, Mika
- Lehtimäki, Terho
- Raitakari, Olli T.
- Lettre, Guillaume
- Franco, Oscar H.
- Rich, Stephen S.
- Rivadeneira, Fernando
- Uitterlinden, André G.
- Psaty, Bruce M.
- Soranzo, Nicole
- Dehghan, Abbas
- Boerwinkle, Eric
- Zhang, Xiaoling
- Johnson, Andrew D.
- O’Donnell, Christopher J.
- Johnsen, Jill M.
- Ganesh, Santhi K.
- Sankaran, Vijay G.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 99
- Issue
- 2
- Pages
- 481-488
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC5011073
- OpenAlex
- W2490904628
- Cited by
- 54
- References
- 33
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 9 · 2019: 6 · 2018: 6 · 2017: 8 · 2016: 4
- FWCI
- 7.61
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-09-01)
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Wellcome Trust (WT 098051, WT091310)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL122684, R33HL120791, R21HL120791)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103794)
- Topics
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- blood cell traits, hematopoiesis, platelet count, CPS1, GFI1B, alternative splicing, splice variants, megakaryopoiesis, hematopoietic stem and progenitor cells, genetic loci, synonymous mutations, missense mutations, quantitative trait loci
- MeSH terms
- Gene Editing, Blood Platelets, DNA Mutational Analysis, Hematopoiesis, Hematopoietic Stem Cells, Humans, Megakaryocytes, Platelet Count, Proto-Oncogene Proteins, Repressor Proteins, Alternative Splicing, Genetic Loci, Exome, CRISPR-Cas Systems
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